Genomic study of taste perception genes in African Americans reveals SNPs linked to Alzheimer's disease.
African American
Alzheimer’s disease
GWAS
Proteome
Taste genes
Transcriptome
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
16 09 2024
16 09 2024
Historique:
received:
05
03
2024
accepted:
29
08
2024
medline:
17
9
2024
pubmed:
17
9
2024
entrez:
16
9
2024
Statut:
epublish
Résumé
While previous research has shown the potential links between taste perception pathways and brain-related conditions, the area involving Alzheimer's disease remains incompletely understood. Taste perception involves neurotransmitter signaling, including serotonin, glutamate, and dopamine. Disruptions in these pathways are implicated in neurodegenerative diseases. The integration of olfactory and taste signals in flavor perception may impact brain health, evident in olfactory dysfunction as an early symptom in neurodegenerative conditions. Shared immune response and inflammatory pathways may contribute to the association between altered taste perception and conditions like neurodegeneration, present in Alzheimer's disease. This study consists of an exploration of expression-quantitative trait loci (eQTL), utilizing whole-blood transcriptome profiles, of 28 taste perception genes, from a combined cohort of 475 African American subjects. This comprehensive dataset was subsequently intersected with single-nucleotide polymorphisms (SNPs) identified in Genome-Wide Association Studies (GWAS) of Alzheimer's Disease (AD). Finally, the investigation delved into assessing the association between eQTLs reported in GWAS of AD and the profiles of 741 proteins from the Olink Neurological Panel. The eQTL analysis unveiled 3,547 statistically significant SNP-Gene associations, involving 412 distinct SNPs that spanned all 28 taste genes. In 17 GWAS studies encompassing various traits, a total of 14 SNPs associated with 12 genes were identified, with three SNPs consistently linked to Alzheimer's disease across four GWAS studies. All three SNPs demonstrated significant associations with the down-regulation of TAS2R41, and two of them were additionally associated with the down-regulation of TAS2R60. In the subsequent pQTL analysis, two of the SNPs linked to TAS2R41 and TAS2R60 genes (rs117771145 and rs10228407) were correlated with the upregulation of two proteins, namely EPHB6 and ADGRB3. Our investigation introduces a new perspective to the understanding of Alzheimer's disease, emphasizing the significance of bitter taste receptor genes in its pathogenesis. These discoveries set the stage for subsequent research to delve into these receptors as promising avenues for both intervention and diagnosis. Nevertheless, the translation of these genetic insights into clinical practice requires a more profound understanding of the implicated pathways and their pertinence to the disease's progression across diverse populations.
Identifiants
pubmed: 39284855
doi: 10.1038/s41598-024-71669-9
pii: 10.1038/s41598-024-71669-9
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
21560Informations de copyright
© 2024. The Author(s).
Références
Chandrashekar, J., Hoon, M. A., Ryba, N. J. & Zuker, C. S. The receptors and cells for mammalian taste. Nature 444(7117), 288–294. https://doi.org/10.1038/nature05401 (2006).
doi: 10.1038/nature05401
pubmed: 17108952
Small, D. M. & Prescott, J. Odor/taste integration and the perception of flavor. Exp. Brain Res. 166(3–4), 345–357. https://doi.org/10.1007/s00221-005-2376-9 (2005).
doi: 10.1007/s00221-005-2376-9
pubmed: 16028032
Kure Liu, C. et al. Brain imaging of taste perception in obesity: A review. Curr. Nutr. Rep. 8(2), 108–119. https://doi.org/10.1007/s13668-019-0269-y (2019).
doi: 10.1007/s13668-019-0269-y
pubmed: 30945140
pmcid: 6486899
Heckmann, J. G. & Lang, C. J. G. Neurological causes of taste disorders. Adv. Otorhinolaryngol. 63, 255–264. https://doi.org/10.1159/000093764 (2006).
doi: 10.1159/000093764
pubmed: 16733343
Ram S, Wada T, Sahai-Srivastava S. Neurosensory Disturbances Including Smell and Taste. In: Farah CS, Balasubramaniam R, McCullough MJ, eds. Contemporary Oral Medicine: A Comprehensive Approach to Clinical Practice. Springer International Publishing, (2018)
Yarmolinsky, D. A., Zuker, C. S. & Ryba, N. J. Common sense about taste: from mammals to insects. Cell 139(2), 234–244. https://doi.org/10.1016/j.cell.2009.10.001 (2009).
doi: 10.1016/j.cell.2009.10.001
pubmed: 19837029
pmcid: 3936514
Howes, O. D. et al. The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch. Gen. Psychiatry 69(8), 776–786. https://doi.org/10.1001/archgenpsychiatry.2012.169 (2012).
doi: 10.1001/archgenpsychiatry.2012.169
pubmed: 22474070
pmcid: 3730746
Nutt, D. J., Lingford-Hughes, A., Erritzoe, D. & Stokes, P. R. The dopamine theory of addiction: 40 years of highs and lows. Nat. Rev. Neurosci. 16(5), 305–312. https://doi.org/10.1038/nrn3939 (2015).
doi: 10.1038/nrn3939
pubmed: 25873042
Doty, R. L. Olfactory dysfunction in neurodegenerative diseases: Is there a common pathological substrate?. Lancet Neurol. 16(6), 478–488. https://doi.org/10.1016/S1474-4422(17)30123-0 (2017).
doi: 10.1016/S1474-4422(17)30123-0
pubmed: 28504111
Steiner, J. E. Human facial expressions in response to taste and smell stimulation. Adv. Child Dev. Behav. 13, 257–295. https://doi.org/10.1016/s0065-2407(08)60349-3 (1979).
doi: 10.1016/s0065-2407(08)60349-3
pubmed: 484324
Dantzer, R., O’Connor, J. C., Freund, G. G., Johnson, R. W. & Kelley, K. W. From inflammation to sickness and depression: When the immune system subjugates the brain. Nat. Rev. Neurosci. 9(1), 46–56. https://doi.org/10.1038/nrn2297 (2008).
doi: 10.1038/nrn2297
pubmed: 18073775
pmcid: 2919277
Medeiros, R., Baglietto-Vargas, D. & LaFerla, F. M. The role of tau in Alzheimer’s disease and related disorders. CNS Neurosci. Ther. 17(5), 514–524. https://doi.org/10.1111/j.1755-5949.2010.00177.x (2011).
doi: 10.1111/j.1755-5949.2010.00177.x
pubmed: 20553310
Sakai, M. et al. Gustatory Dysfunction as an Early Symptom of Semantic Dementia. Dement. Geriatr. Cogn. Dis. Extra. 7(3), 395–405. https://doi.org/10.1159/000481854 (2017).
doi: 10.1159/000481854
pubmed: 29430242
pmcid: 5806165
Sakai, M., Ikeda, M., Kazui, H., Shigenobu, K. & Nishikawa, T. Decline of gustatory sensitivity with the progression of Alzheimer’s disease. Int. Psychogeriatr. 28(3), 511–517. https://doi.org/10.1017/s1041610215001337 (2016).
doi: 10.1017/s1041610215001337
pubmed: 26423603
Schiffman, S. S., Graham, B. G., Sattely-Miller, E. A., Zervakis, J. & Welsh-Bohmer, K. Taste, smell and neuropsychological performance of individuals at familial risk for Alzheimer’s disease. Neurobiol. Aging https://doi.org/10.1016/S0197-4580(01)00337-2 (2002).
doi: 10.1016/S0197-4580(01)00337-2
pubmed: 11959402
Steinbach, S. et al. Taste in mild cognitive impairment and Alzheimer’s disease. J. Neurol. 257(2), 238–246. https://doi.org/10.1007/s00415-009-5300-6 (2010).
doi: 10.1007/s00415-009-5300-6
pubmed: 19727902
Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 45(12), 1452–1458. https://doi.org/10.1038/ng.2802 (2013).
doi: 10.1038/ng.2802
pubmed: 24162737
pmcid: 3896259
Marioni, R. E. et al. GWAS on family history of Alzheimer’s disease. Transl. Psychiatry https://doi.org/10.1038/s41398-018-0150-6 (2018).
doi: 10.1038/s41398-018-0150-6
pubmed: 29777097
pmcid: 5959890
Moreno-Grau, S. et al. Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer’s disease and three causality networks: The GR@ACE project. Alzheimers Dement. 15(10), 1333–1347. https://doi.org/10.1016/j.jalz.2019.06.4950 (2019).
doi: 10.1016/j.jalz.2019.06.4950
pubmed: 31473137
Bellenguez, C. et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat Genet. 54(4), 412–436. https://doi.org/10.1038/s41588-022-01024-z (2022).
doi: 10.1038/s41588-022-01024-z
pubmed: 35379992
pmcid: 9005347
Jansen, I. E. et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat Genet. 51(3), 404–413. https://doi.org/10.1038/s41588-018-0311-9 (2019).
doi: 10.1038/s41588-018-0311-9
pubmed: 30617256
pmcid: 6836675
Lennon, J. C. et al. Black and White individuals differ in dementia prevalence, risk factors, and symptomatic presentation. Alzheimers Dement. 18(8), 1461–1471. https://doi.org/10.1002/alz.12509 (2022).
doi: 10.1002/alz.12509
pubmed: 34854531
Association As. Black Americans and alzheimer's. https://www.alz.org/help-support/resources/black-americans-and-alzheimers , (Accessed 02 May 2024).
Institute B. broadinstitute/gtex-pipeline. https://github.com/broadinstitute/gtex-pipeline
Robinson, M. D. & Oshlack, A. A scaling normalization method for differential expression analysis of RNA-seq data. Genome Biol. 11(3), R25. https://doi.org/10.1186/gb-2010-11-3-r25 (2010).
doi: 10.1186/gb-2010-11-3-r25
pubmed: 20196867
pmcid: 2864565
Sollis, E. et al. The NHGRI-EBI GWAS Catalog: knowledgebase and deposition resource. Nucleic Acids Res. 51(D1), D977–D985. https://doi.org/10.1093/nar/gkac1010 (2023).
doi: 10.1093/nar/gkac1010
pubmed: 36350656
Shabalin, A. A. Matrix eQTL: Ultra fast eQTL analysis via large matrix operations. Bioinformatics 28(10), 1353–1358. https://doi.org/10.1093/bioinformatics/bts163 (2012).
doi: 10.1093/bioinformatics/bts163
pubmed: 22492648
pmcid: 3348564
Avau, B. & Depoortere, I. The bitter truth about bitter taste receptors: beyond sensing bitter in the oral cavity. Acta Physiol. (Oxf). 216(4), 407–420. https://doi.org/10.1111/apha.12621 (2016).
doi: 10.1111/apha.12621
pubmed: 26493384
Carey, R. M. & Lee, R. J. Taste receptors in upper airway innate immunity. Nutrients https://doi.org/10.3390/nu11092017 (2019).
doi: 10.3390/nu11092017
pubmed: 31487854
pmcid: 6769900
Duarte, A. C. et al. Bitter taste receptors profiling in the human blood-cerebrospinal fluid-barrier. Biochem. Pharmacol. https://doi.org/10.1016/j.bcp.2020.113954 (2020).
doi: 10.1016/j.bcp.2020.113954
pubmed: 32272108
pmcid: 9116130
Duarte, A. C. et al. The druggability of bitter taste receptors for the treatment of neurodegenerative disorders. Biochem. Pharmacol. https://doi.org/10.1016/j.bcp.2022.114915 (2022).
doi: 10.1016/j.bcp.2022.114915
pubmed: 35182520
Lu, P., Zhang, C. H., Lifshitz, L. M. & ZhuGe, R. Extraoral bitter taste receptors in health and disease. J. Gen. Physiol. 149(2), 181–197. https://doi.org/10.1085/jgp.201611637 (2017).
doi: 10.1085/jgp.201611637
pubmed: 28053191
pmcid: 5299619
de Jesus, V. C., Mittermuller, B. A., Hu, P., Schroth, R. J. & Chelikani, P. Association between downstream taste signaling genes, oral microbiome, and severe early childhood caries. Int. J. Mol. Sci. https://doi.org/10.3390/ijms24010081 (2022).
doi: 10.3390/ijms24010081
pubmed: 36613519
pmcid: 9820665
Harmon, C. P., Deng, D. & Breslin, P. A. S. Bitter taste receptors (T2Rs) are sentinels that coordinate metabolic and immunological defense responses. Curr. Opin. Physiol. 20, 70–76. https://doi.org/10.1016/j.cophys.2021.01.006 (2021).
doi: 10.1016/j.cophys.2021.01.006
pubmed: 33738371
pmcid: 7963268
da Silva, E. C. et al. Characterization of the porcine nutrient and taste receptor gene repertoire in domestic and wild populations across the globe. BMC Genomics. https://doi.org/10.1186/1471-2164-15-1057 (2014).
doi: 10.1186/1471-2164-15-1057
pubmed: 25573652
pmcid: 4326474
Behrens, M. & Meyerhof, W. Gustatory and extragustatory functions of mammalian taste receptors. Physiol. Behav. 105(1), 4–13. https://doi.org/10.1016/j.physbeh.2011.02.010 (2011).
doi: 10.1016/j.physbeh.2011.02.010
pubmed: 21324331
Xi, R., Zheng, X. & Tizzano, M. Role of taste receptors in innate immunity and oral health. J. Dent. Res. 101(7), 759–768. https://doi.org/10.1177/00220345221077989 (2022).
doi: 10.1177/00220345221077989
pubmed: 35191336
pmcid: 9218499
Welcome, M. O., Dogo, D. & Nikos, E. M. Cellular mechanisms and molecular pathways linking bitter taste receptor signalling to cardiac inflammation, oxidative stress, arrhythmia and contractile dysfunction in heart diseases. Inflammopharmacology 31(1), 89–117. https://doi.org/10.1007/s10787-022-01086-9 (2023).
doi: 10.1007/s10787-022-01086-9
pubmed: 36471190
Welcome, M. O. & Mastorakis, N. E. The taste of neuroinflammation: Molecular mechanisms linking taste sensing to neuroinflammatory responses. Pharmacol. Res. https://doi.org/10.1016/j.phrs.2021.105557 (2021).
doi: 10.1016/j.phrs.2021.105557
pubmed: 33737243
Guzman-Martinez, L. et al. Neuroinflammation as a Common Feature of Neurodegenerative Disorders. Front. Pharmacol. 10, 1008. https://doi.org/10.3389/fphar.2019.01008 (2019).
doi: 10.3389/fphar.2019.01008
pubmed: 31572186
pmcid: 6751310
Tuzim, K. & Korolczuk, A. An update on extra-oral bitter taste receptors. J. Transl. Med. https://doi.org/10.1186/s12967-021-03067-y (2021).
doi: 10.1186/s12967-021-03067-y
pubmed: 34836552
pmcid: 8620548
Dong, G., Boothe, K., He, L., Shi, Y. & McCluskey, L. P. Altered peripheral taste function in a mouse model of inflammatory bowel disease. Res. Sq. https://doi.org/10.21203/rs.3.rs-3304297/v1 (2023).
doi: 10.21203/rs.3.rs-3304297/v1
pubmed: 38196646
pmcid: 10775378
Liu, T., Zhang, L., Joo, D. & Sun, S. C. NF-kappaB signaling in inflammation. Signal Transduct. Target Ther. https://doi.org/10.1038/sigtrans.2017.23 (2017).
doi: 10.1038/sigtrans.2017.23
pubmed: 29266131
pmcid: 5701083
Kinney, J. W. et al. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement (N Y). 4, 575–590. https://doi.org/10.1016/j.trci.2018.06.014 (2018).
doi: 10.1016/j.trci.2018.06.014
pubmed: 30406177
Wooding, S. P. & Ramirez, V. A. Global population genetics and diversity in the TAS2R bitter taste receptor family. Front. Genet. https://doi.org/10.3389/fgene.2022.952299 (2022).
doi: 10.3389/fgene.2022.952299
pubmed: 36303543
pmcid: 9592824
Kania, A. & Klein, R. Mechanisms of ephrin-Eph signalling in development, physiology and disease. Nat. Rev. Mol. Cell Biol. 17(4), 240–256. https://doi.org/10.1038/nrm.2015.16 (2016).
doi: 10.1038/nrm.2015.16
pubmed: 26790531
Sloniowski, S. & Ethell, I. M. Looking forward to EphB signaling in synapses. Semin Cell Dev. Biol. 23(1), 75–82. https://doi.org/10.1016/j.semcdb.2011.10.020 (2012).
doi: 10.1016/j.semcdb.2011.10.020
pubmed: 22040917
He, C. H. et al. Overexpression of EphB6 and EphrinB2 controls soma spacing of cortical neurons in a mutual inhibitory way. Cell Death Dis. https://doi.org/10.1038/s41419-023-05825-w (2023).
doi: 10.1038/s41419-023-05825-w
pubmed: 38129399
pmcid: 10739961
Darling, T. K. & Lamb, T. J. Emerging roles for eph receptors and ephrin ligands in immunity. Front Immunol. 10, 1473. https://doi.org/10.3389/fimmu.2019.01473 (2019).
doi: 10.3389/fimmu.2019.01473
pubmed: 31333644
pmcid: 6620610
Dal Pra, I., Armato, U. & Chiarini, A. Family C G-protein-coupled receptors in Alzheimer’s disease and therapeutic implications. Front Pharmacol. 10, 1282. https://doi.org/10.3389/fphar.2019.01282 (2019).
doi: 10.3389/fphar.2019.01282
Lanoue, V. et al. The adhesion-GPCR BAI3, a gene linked to psychiatric disorders, regulates dendrite morphogenesis in neurons. Mol. Psychiatry https://doi.org/10.1038/mp.2013.46 (2013).
doi: 10.1038/mp.2013.46
pubmed: 23628982
pmcid: 3730300
Stephenson, J. R. et al. Brain-specific angiogenesis inhibitor-1 signaling, regulation, and enrichment in the postsynaptic density. J. Biol. Chem. 288(31), 22248–22256. https://doi.org/10.1074/jbc.M113.489757 (2013).
doi: 10.1074/jbc.M113.489757
pubmed: 23782696
pmcid: 3829316
Shiu, F. H. et al. Mice lacking full length Adgrb1 (Bai1) exhibit social deficits, increased seizure susceptibility, and altered brain development. Exp. Neurol. 351, 113994. https://doi.org/10.1016/j.expneurol.2022.113994 (2022).
doi: 10.1016/j.expneurol.2022.113994
pubmed: 35114205
pmcid: 9817291
Choi, J. S., Bae, W. Y., Nam, S. & Jeong, J. W. New targets for Parkinson’s disease: Adhesion G protein-coupled receptor B1 is downregulated by AMP-activated protein kinase activation. OMICS 22(7), 493–501. https://doi.org/10.1089/omi.2018.0047 (2018).
doi: 10.1089/omi.2018.0047
pubmed: 30004846
Choi, J. S., Park, C. & Jeong, J. W. AMP-activated protein kinase is activated in Parkinson’s disease models mediated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Biochem. Biophys. Res. Commun. 391(1), 147–151. https://doi.org/10.1016/j.bbrc.2009.11.022 (2010).
doi: 10.1016/j.bbrc.2009.11.022
pubmed: 19903456
Purcell, R. H. & Hall, R. A. Adhesion G protein-coupled receptors as drug targets. Annu. Rev. Pharmacol. Toxicol. 58, 429–449. https://doi.org/10.1146/annurev-pharmtox-010617-052933 (2018).
doi: 10.1146/annurev-pharmtox-010617-052933
pubmed: 28968187
Lala, T. & Hall, R. A. Adhesion G protein-coupled receptors: Structure, signaling, physiology, and pathophysiology. Physiol. Rev. 102(4), 1587–1624. https://doi.org/10.1152/physrev.00027.2021 (2022).
doi: 10.1152/physrev.00027.2021
pubmed: 35468004
pmcid: 9255715
Scuderi, C. et al. Biallelic intragenic duplication in ADGRB3 (BAI3) gene associated with intellectual disability, cerebellar atrophy, and behavioral disorder. Eur. J. Hum. Genet. 27(4), 594–602. https://doi.org/10.1038/s41431-018-0321-1 (2019).
doi: 10.1038/s41431-018-0321-1
pubmed: 30659260
pmcid: 6460634
Bipolar D, Schizophrenia Working Group of the Psychiatric Genomics Consortium. Electronic address drve, Bipolar D, Schizophrenia Working Group of the Psychiatric Genomics C. Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes. Cell. https://doi.org/10.1016/j.cell.2018.05.046 , (2018).
Zehentner S, Reiner AT, Grimm C, Somoza V. The Role of Bitter Taste Receptors in Cancer: A Systematic Review. Cancers (Basel). Nov 23 2021;13(23) https://doi.org/10.3390/cancers13235891
Minocha, T. et al. Flavonoids as promising neuroprotectants and their therapeutic potential against Alzheimer’s disease. Oxid. Med. Cell. Longev. 2022, 6038996. https://doi.org/10.1155/2022/6038996 (2022).
doi: 10.1155/2022/6038996
pubmed: 36071869
pmcid: 9441372
Nayak, A. P., Villalba, D. & Deshpande, D. A. Bitter taste receptors: An answer to comprehensive asthma control?. Curr. Allergy Asthma. Rep. https://doi.org/10.1007/s11882-019-0876-0 (2019).
doi: 10.1007/s11882-019-0876-0
pubmed: 31486942
pmcid: 6765386
Oatman, S. R. et al. Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer’s disease related proteins. Mol. Neurodegener. https://doi.org/10.1186/s13024-022-00592-2 (2023).
doi: 10.1186/s13024-022-00592-2
pubmed: 36609403
pmcid: 9825010
Romano, R. R. 3rd., Carter, M. A. & Monroe, T. B. Narrative review of sensory changes as a biomarker for Alzheimer’s disease. Biol Res Nurs. 23(2), 223–230. https://doi.org/10.1177/1099800420947176 (2021).
doi: 10.1177/1099800420947176
pubmed: 32799655